Beta cells of the pancreas, which make and secrete insulin, do not respond like those of non-diabetic subjects when type 2 diabetes is present. Specifically, subjects suffering from type 2 diabetes have a blunted or even absolute loss of first phase and a severely blunted second phase insulin release in response to glucose. In conjunction with this, and despite all treatments currently available to treat diabetes, beta cell function continues to deteriorate over time. With the data now available from the United Kingdom Prospective Diabetes Study (Sept. 1998) this point was brought home even more forcefully. Despite continual monitoring of patients enrolled in the study, euglycemia could not be maintained even with intensive therapy, because of declining beta cell function. We have been working for some time with GLP-1, a naturally occurring peptide produced and released from the gut in response to food. Of great interest is the finding that in type2 diabetes, pharmacological doses of GLP-1 can normalize blood sugars, i.e. euglycemia is achieved. However, GLP-1 has a biological half-life of only 2-4 minutes and has to be given systemically. Its short half-life is partially due to rapid inactivation of the peptide by dipeptidyl peptidase IV (DPP IV) which cleaves off the first 2 amino acids. This means that it would have to be given continuously in order to maintain euglycemia. The Gila monster is a lizard whose natural habitat is in Arizona. It produces a peptide, called exendin-4, in its saliva which is an agonist of the GLP-1 receptor. Exendin-4 has a unique 9 amino acid N-terminal tail, not present on GLP-1. We have been investigating the function of those 9 amino acids and their relationship to biological activity and length-of-action of Exendin-4. So we have systemically removed them from exendin-4 and added them to the GLP-1. Our findings support the notion that the 9 amino acids improve the metabolic stability of GLP-1 when added to GLP-1 and enhance its affinity for its specific receptor. More recently, we have been working on a GLP-1 fusion protein, whereby GLP-1 is fused to transferrin, thus extending its half-life, in vitro, by several days. We are now carrying out the in vivo work to delineate its kinetics and dosing schedules.
Showing the most recent 10 out of 15 publications
